Late adverse effects of radiation therapy for rectal cancer – a systematic overview

Figures & data

Table I.  List of meta-analyses and reviews on late adverse effects of radiation therapy for rectal cancer. The publications are listed in order of year of publication and comments are made on the publication.

Reference	Year of publication	Comments
Meta-analyses
Colorectal Cancer Collaborative Group [1]	2001	Meta-analysis of 22 randomised trials comparing outcomes of surgery including non-colorectal cancer mortality
Glimelius et al. [2]	2003	Systemic overview of 131 scientific articles with the secondary aim of analysing late adverse effects, mainly bowel function and gastrointestinal disorders
Bakx et al. [26]	2006	A model study of 4 randomised trials balancing gains and losses of preop RT 5×5 Gy
Reviews
Cummings [29]	1986	A critical review of preoperative RT
Gerard et al. [31]	1995	A review on dose volume relationship in the risk of radiation induced rectal complications
Letschert [34]	1995	A review of radiation-induced small bowel complications and its prevention
Coia [28]	1995	A comprehensive review discussing tolerance doses and management on late adverse effects of RT on the GI tract
Camilleri-Brennan et al. [27]	1998	A review of 54 studies on quality of life in rectal cancer surgery, which discusses a few studies including RT and CT
Ooi et al. [35]	1999	A review mainly discussing early adverse effects of RT and CT for rectal cancer, but also commenting on late adverse effects
Johnston et al. [33]	2003	Review considering the management of late adverse effects of pelvic RT
Temple et al. [36]	2003	A review mainly discussing anal and sexual dysfunction of RT for rectal cancer
Fajardo [30]	2005	Pathological description of the effects of RT on normal tissues
Guckenberger and Flentje [32]	2005	Review on late small bowel toxicity after adjuvant treatment for rectal cancer

Abbreviations: RT: Radiation therapy; CT: Chemotherapy; CRT: Chemo radiotherapy; Gy: Gray.

Table II.  List of randomised clinical trials on late adverse effects of radiation therapy for rectal cancer. The publications are listed in order of year of publication. Comments are made on the follow-up time in years, type of study, radiation technique, and the late adverse effects reported.

Reference	Year of publication	Follow-up in years	Type of study	Type of radiation	Adverse effects reported
Dahl et al. [37]	1990	5	Examination	Preop 18×1.75 Gy vs no RT	BF, U
Frykholm et al. [42]	1993	8–10	Hospital records and interview	Preop 5×5 Gy vs postop 25×2 Gy for II and III	BF, GI, U, D
Holm et al. [41]	1996	5	Register study	Preop 5×5 Gy vs no RT	F, GI, U, V
MRC-2 [44]	1996	5	Interview	Preop 20×2 Gy vs no RT	GI, U
MRC-3 [45]	1996	5	Interview	Postop 20×2 Gy vs no RT	GI, U
Lundby et al. [39]	1997	14	Questionnaire telephone	Postop 25×2 Gy vs no RT	BF
Dahlberg et al. [22]	1998	5	Questionnaire	Preop 5×5 Gy vs no RT	BF, QLB
Sauer et al. [16]	2004	5	Prospective registration	Preop CRT 28×1.8 Gy + 5-FU vs postop 28×1.8 Gy + 5-FU	BF, D, GI, H, U
Birgisson et al. [21]	2005	13	Register study	Preop 5×5 Gy vs no RT	All organs
Birgisson et al. [23]	2005	13	Register study	Preop 5×5 Gy vs no RT	Second cancers
Marijnen et al. [7]	2004	2	Questionnaire	Preop 5×5 Gy vs no RT	SF, QL
Peeters et al. [20]	2005	5	Questionnaire	Preop 5×5 Gy vs no RT	BF, GI, QL, SF, U, V
Lundby et al. [40]	2005	17	Examination	Postop 25×2 Gy vs no RT	BF
Pollack et al. [38]	2006	14	Examination	Preop 5×5 Gy vs no RT	BF, QL, GI, U, V
Pollack et al. [25]	2006	14	Examination	Preop 5×5 Gy vs no RT	BF
Bujko et al. [43]	2006	4	Examination	Preop 5×5 Gy vs preop 28×1.8 Gy + 5-FU	F, GI, N, U

Abbreviations: RT: Radiation therapy; CT: Chemotherapy; CRT: Chemo radiotherapy; Gy: Gray; y: Years; 5-FU: 5-fluorouracil; Preop: Preoperative; Postop: Postoperative; BF: Bowel dysfunction; D: Dermatological problems; F: Fractures; GI: Gastrointestinal; H: Haematological; N: Neurological; QL: Quality of Live; QLB: Quality of life related to bowel function; SF: Sexual dysfunction; U: Urinary tract; V: Vascular.

Table III.  List of cohort and case-control studies on late adverse effects of radiation therapy for rectal cancer. The publications are listed in order of year of publication. Comments are made on the follow-up time in years, type of study, radiation technique, and the late adverse effects reported.

Reference	Year of publication	Follow-up in years	Type of study	Type of radiation	Adverse effects reported
Letschert et al. [50]	1990	2	Hospital records	Postop 22–25×2 Gy	GI
Birnbaum et al. [46]	1994	3	Examination	Preop 25×1.8 Gy	BF
Kollmorgen et al. [49]	1994	2-5	Telephone Questionnaire	Postop CRT vs no RT	BF
Mak et al. [52]	1994	3–21	Hospital records	Postop various	GI, U
Lewis et al. [51]	1995	1	Questionnaire/Examination	Postop CRT vs no RT	BF
Minsky et al. [54]	1995	3	Questionnaire/Examination	Preop 28×1.8 Gy	BF
Wagman et al. [58]	1998	5	Examination	Preop 27×1.8 Gy±CT	BF
Miller et al. [53]	1999	5	Hospital records	Postop CRT	BF, GI
Olagne et al. [56]	2000	3	Questionnaire	Preop 25×1.8 Gy	BF
Caffo et al. [47]	2002	3	Questionnaire	Postop 25–30×1.8 Gy±5-FU	QL
Dehni et al. [48]	2002	3	Questionnaire/Examination	Preop 5×5 Gy or 25×1.8 Gy vs no RT	BF
van Duijvendijk et al. [59]	2002	1	Questionnaire/Examination	Preop 5×5 Gy vs no RT	BF, U
Prabhudesai et al. [57]	2005	1	Questionnaire/Examination	Preop 5×5 Gy vs no RT	BF, D, GI, U
Mohiuddin et al. [55]	2006	2–5	Examination	Preop CRT 46-50×1.2 Gy with 5-FU vs 5-FU + irinotecan	D, GI, U

Abbreviations: RT: Radiation therapy; CT: Chemotherapy; CRT: Chemo radiotherapy; Gy: Gray; y: Years; 5-FU: 5-fluorouracil; Preop: Preoperative; Postop: Postoperative; BF: Bowel dysfunction; D: Dermatological problems; GI: Gastrointestinal; QL: Quality of Live; U: Urinary tract.

Table IV.  List of randomised trials on radiation therapy for rectal cancer dealing with late adverse effects. The year of study, type of radiation in each arm, the radiation technique, upper beam limits, and whether or not the irradiation of anal sphincters was made, are presented.

Study	Year	Arm I Dose (Gy)/Fraction (n)*	Arm II Dose (Gy)/Fraction (n)*	RT Technique Beams	Upper beam limits	Irradiation of anal sphincters
Western Norwegian Trial [37]	1976–85	Preop 31.5/18 (159)	no RT (150)	AP–PA	L1/L2	For tumours <5 cm from anus
Uppsala Trial [42]	1980–85	Preop 25/5 (236)	Postop 50/25 (235)	3	L 4	For tumours <10 cm from anus
Stockholm I [25], [38], [41]	1980–87	Preop 25/5 (424)	no RT (425)	AP–PA	L 2	All patients
MRC-2 [44]	1981–89	Preop 40/20 (139)	no RT (140)	AP–PA	5 cm above tumour	na
MRC-3 [45]	1984–89	no RT (235)	Postop 40/20 (234)	AP–PA	5 cm above tumour	If APR was done
Stockholm II [25], [41]	1987–93	Preop 25/5 (272)	no RT (285)	3/4	L 4	All patients
SRCT [21–23]	1987–90	Preop 25/5 (572)	no RT (575)	3/4	L 4	All patients
Dutch TME trial [20], [24]	1996–99	Preop 25/5 (924)	no RT (937)	3/4	L 5/S 1	If APR was planned
German trial [16]	1995–02	Preop 50.4/28 + CT (421)	Postop 50,4/28 + CT (402)	3/4	L 4/L 5	If ≤2 cm from dentate line
Danish [39], [40]	1979–85	no RT (250)	Postop 50/25 (244)	AP–PA	L5	na
Polish trial [43]	1999–02	Preop 25/5 (155)	Preop 50.4/28 + CT (157)	3/4	L 5/S 1	All patients

RT: Radiation therapy; CT: Chemotherapy; Gy: Gray; Preop: Preoperative; Postop: Postoperative; L: Lumbar vertebrae; y: years; MRC: Medical research council rectal cancer working party; TME: Total mesorectal excision; SRCT: Swedish rectal cancer trial; APR: Abdominoperineal rectal excision; na: Not available. * Number of patients allocated to each treatment arm. S: Sacral vertebrae; AP–PA: Anterior posterior – Posterior anterior; 3/4: Three or four.

Table V.  RTOG/EORTC late radiation morbidity scoring schema for adverse gastrointestinal effects.

ORGAN TISSUE	0	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
SMALL OR LARGE INTESTINE	None	Mild diarrhoea	Moderate diarrhoea and colic	Obstruction or bleeding requiring surgery	Necrosis/ Perforation Fistula	Death directly related to the radiation effects
		Mild cramping	Bowel movement >5 times daily
		Bowel movement 5 times daily	Excessive rectal mucus or intermittent bleeding
		Slight rectal discharge or bleeding

RTOG: Radiation Therapy Oncology Group.

EORTC: European Organisation for Research and Treatment of Cancer.

Table VI.  A comparison of faecal incontinence in patients treated for rectal cancer with RT and low anterior resection or low anterior resection alone. The results are from randomised clinical trials that have studied late bowel dysfunction.

	Faecal incontinence		Faecal incontinence Night		Faecal incontinence Loose stools		Faecal incontinence Solid stools
	Preop RT %	No RT %	RT %	No RT %	RT %	No RT %	RT %	No RT %
Dahlberg et al. [22]	#	#	14	8 ns	50	24*	14	3*
Peeters et al. [20]	62	38*	32	17*	#	#	#	#
Pollack et al. [25]	57	26*	#	#	#	#	#	#
	Postop RT %		Postop RT %		Postop RT %		Postop RT %
Lundby et al. [39]	49	5*	#	#	#	#	#	#
Lundby et al. [40]	60	8*	#	#	#	#	#	#

RT: Radiation therapy; CRT: Chemo radiotherapy; Preop: Preoperative; Postop: Postoperative; ns: Non-significant; *: Significant (p < 0.05), #: Not analysed.

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